Complement receptor 1 (CR1) is a type I transmembrane glycoprotein, that inhibits pivotal steps in complement activation cascades. A recombinant, soluble form of CR1 (sCR1) has also been shown to inhibit complement activation in a number of animal disease states and is currently in human clinical trials. Blood group antibodies made in response to alloimmunization and autoantibodies (in patients with autoimmune hemolytic disease) can cause complement-mediated red cell destruction. The potential of sCR1 as an inhibitor of complement activation in transfusion-associated hemolytic diseases has important clinical implications which have yet to be explored. Moreover, CR1, through its the complement binding domains and blood group associated Knops antigens has been shown to mediate rosetting by certain strains of Plasmodium falciparum , a phenomenon linked to severe malarial infection. The purpose of this proposal is to perform structure-function analysis on the CR1 protein to gain clinically useful information about its interactions with its ligands in two contexts. By performing site-directed mutagenesis on CR1 and subsequent in vitro assays with the expressed proteins, we propose: (1) to determine the functional regions of the CR1 protein that can inhibit complement activation encountered in allo- and autoimmune hemolytic diseases; (2) to identify the domains of CR1 which interacts with the malarial rosetting ligand. Information gained from these studies can direct the design of chemotherapeutic agents to inhibit complement activation in transfused patients and provide concrete guidelines for the design of drugs by which to prevent malarial rosetting.